Compounds of the general formula I as defined above are known from WO00/29397 and WO01/85725. These compounds show varying activities as either partial agonists or agonists at the dopamine D2 receptor and are also agonists of the 5HT1A receptor. These combinations of activities make the compounds of value for the treatment of afflictions and diseases of the central nervous system caused by disturbances in either the dopaminergic or serotonergic systems, for example, in Parkinson's disease and restless leg syndrome.
In certain cases, e.g., when oral delivery or injection of a particular pharmaceutically active compound (also referred to as a drug) may be ineffective or unacceptable because of poor gastrointestinal absorption, an extensive first pass effect, patient pain and discomfort, or other side effects or drawbacks, transdermal delivery may provide an advantageous method of delivering that compound. This is the case, for example, for Parkinson's disease, where there is a need to administer medication to patients who are sleeping, comatose or anaesthetized. Further, there is growing evidence that continuous dopamine stimulation avoids the development of problems associated with intermittent dosing and where continuous drug delivery has been shown to decrease the incidence of “off” periods (P. Niall and W. H. Oertel, Congress Report of 7th International Congress of Parkinson's Disease and Movement Disorders, Miami, Fla., Nov. 10-14, 2002). In general, transdermal administration also has its problems, since it is not always easy to get drugs to cross the skin.
Iontophoretic transdermal delivery relates to introducing ions or soluble salts of pharmaceutically active compounds into tissues of the body under the influence of an applied electric field.
The features and benefits of iontophoretic transdermal delivery systems as compared with passive transdermal systems, as well as with other means of delivering pharmaceutical compounds into the bloodstream have e.g. been reviewed in O. Wong, “Iontophoresis: Fundamentals,” in Drugs Pharm. Sci. (1994), 62 (Drug Permeation Enhancement), 219-46 (1994); P. Singh et al., “Iontophoresis in Drug Delivery: Basic Principles and Applications”, Critical Reviews in Therapeutic Drug Carrier Systems, 11 (2 & 3): 161-213 (1994); and Ajay K. Banga, Electrically Assisted Transdermal and Topical Drug Delivery, Taylor and Francis Group Ltd., London UK, 1998, ISBN 0-7484-0687-5.
In certain cases, e.g., when transdermal delivery by means of patches appears to be ineffective or unacceptable because of low passage through the skin, leading to very large patches, iontophoretic transdermal delivery may provide an advantageous method of delivering that compound. Further iontophoretic transdermal delivery has the major advantage that the administered amount can be regulated precisely and can be used to easily titrate patients up to a certain level of administration over a period of up to several weeks.
Despite these advantages, iontophoretic methods appear limited as the drug delivery profile of a particular method depends heavily on the particular drug administered. Although a lot of experiments have been done with the iontophoretic delivery of various active substances, specific information allowing a person skilled in the art to tailor the delivery profile of a specific drug is not always available.
As it has appeared that it is very difficult to develop transdermal patches with an acceptable size for compounstipkds with the general formula (I), there is a need for an iontophoretic delivery method for said compounds that allows variable rate delivery of said compounds tailored to a specific treatment.